This invention relates to fluorescence-guided nerve imaging during surgery, specifically to the field of intraoperative topical administration of myelin basic protein (MBP) nerve imaging contrast agents. Also provided are pharmaceutical formulations for topical administration of the contrast agents to allow for intraoperative nerve identification.
Unintended nerve injury is a leading cause of morbidity associated with many lifesaving surgical procedures. Complications arising from these injuries are dependent on the severity and location of the nerve injury and often result in symptoms that negatively impact the patient's quality of life, such as loss of function and/or sensation, muscle atrophy, paralysis, and chronic neuropathy. Cancer surgery requiring radical resection in the abdomen and pelvis is of particular importance, as many small nerves are involved in sensory, motor, and autonomic functions. In colorectal and gynecologic surgery, preservation of autonomic nerves that control the bladder and bowel is of utmost importance after achieving cancer control. In the field of urology, outcome studies following radical prostatectomy showed that urinary and sexual dysfunction were common even 5 years following the procedure as a result of nerve damage. These nerves in the neurovascular bundle are often difficult to visualize during surgery, even under magnification, due to their intricacy, size, and anatomic variations among individuals. The causes of nerve injury are varied but often results from limited ability to distinguish nerve fibers from the surrounding tissue; they can be mistaken for vessels, or they can be resected along with the targeted malignancy because of their proximity. Current nerve-sparing techniques rely primarily upon anatomic landmark identification, which is highly dependent on the surgeon's experience.
Intraoperative identification of nerves has been successfully demonstrated using fluorescence image-guided surgery in preclinical studies using systemically injected contrast agents (cite our patents and publications). Following intravenous (IV) injection in animals, sufficient time is needed to allow the contrast agent to distribute into the whole body, target the specific protein, and clear from the non-target areas. Since fluorescence-guided surgery was first used, few targeted optical agents have been tested in humans. There is a barrier to clinical translation because of the regulatory oversight on testing systemically administered contrast agents into human. Topical administration has the potential to lower the cost of the clinical development program, making the transition to human studies more feasible.
Compared to systemic delivery of contrast agent, the topical application has many potential advantages. It could potentially limit the possibility of systemic absorption and toxicity thereby enhancing the safety profile of the contrast agent. It could produce high and sustained dose of the contrast agent at the surgical site, where intraoperative visualization is most needed, while limiting the concentration elsewhere. It would also allow the surgeons to control the timing of topical application, so that they can apply it at the surgical site when needed.
Thus, a need for a topical agent that can label nerves exists.